Dr. Liang's career goals include becoming an independent clinical investigator with expertise in cardiorenal failure, volume management, and assessment of health-related quality of life (HRQOL). She aims to become an academic nephrologist capable of developing clinical trials and translating that work into clinical care in order to improve outcomes and HRQOL in the cardiorenal failure population. Her training in clinical nephrology, including the care of many patients with cardiorenal failure, and her previous clinical research experiences using existing data sets, have provided her with a strong foundation to pursue further clinical research with human subjects. Her track record suggests that mentorship and research activities from the K23 Mentored Patient-Oriented Research Career Development Award would enable her to develop a research career that will make a new contribution to the care of patients with acute decompensated heart failure (HF) and volume overload. Cardiorenal failure and cardiorenal syndrome are increasingly recognized in patients with HF. In patients with cardiorenal syndrome, attempts at diuresis often exacerbate underlying renal dysfunction. Worsening renal function, typically defined as a rise in serum creatinine of e 0.3 mg/dL, is associated with worse outcomes, chronic volume overload, and worse HRQOL. When medical therapies fail to alleviate congestion, ultrafiltration (UF) may be used for mechanical fluid removal and is endorsed by current HF treatment guidelines. Timely fluid removal may prevent or abolish worsening renal function by reducing renal venous congestion and renal interstitial pressure. There is a critical gap in the literature regarding when to initiae UF in order to improve outcomes and HRQOL. Dr. Liang's proposed study aims to determine whether early initiation of UF in a novel treatment protocol, as opposed to usual clinical care, is associated with improved clinical outcomes and HRQOL in hospitalized cardiorenal failure patients with diuretic resistance. Dr. Liang is an ideal candidate to carry out the proposed investigation. She has completed research investigating clinical outcomes of 11 patients using a peripheral UF device in advanced HF, as well as a study assessing the relationship between hospitalized HF and chronic renal replacement therapy over a 16-year time period. She has authored two review articles in the field of acute decompensated HF and the role of UF in HF. The proposed work follows seamlessly along her prior contributions to the field of cardiorenal failure, with the innovative concept that earlier UF initiation will lead to better outcomes than standard clinical care. She will conduct a small prospective randomized study of hospitalized HF patients with underlying renal dysfunction (estimated glomerular filtration rate (GFR) 15-59 mL/min) treated with either protocolized treatment with early UF after failing medical therapy for 48 hours, or usual care. Patients will be followed with clinical parameters and HRQOL surveys during hospital admission and at short-term (30-day) and long-term (90-day) follow-up after discharge. This study will address key gaps in knowledge and will help determine the appropriate treatment strategy and timing of UF in this large population with poor HRQOL, substantial healthcare costs, and high morbidity and mortality. The Specific Aims are: Specific Aim 1. To determine whether short-term and long-term renal endpoints improve, including improved renal function (based on creatinine, cystatin C, and estimated GFR) and reduced need for chronic renal replacement therapy, after early initiation of UF compared to usual care. Specific Aim 2. To assess short-term and long-term clinical endpoints, including length of hospitalization and number of rehospitalizations, after early initiation of UF compared to usual care. Specific Aim 3. To determine whether short-term and long-term HRQOL outcomes improve after early initiation of UF compared to usual care. The goals of this project are: 1) To determine the appropriate use and timing of UF as a treatment strategy in cardiorenal failure; 2) To improve outcomes and HRQOL in patients with cardiorenal failure through improved therapies; and 3) To provide feasibility data for patient recruitment, enrollment, and retention fo future larger randomized controlled trials. This grant will provide Dr. Liang with hands-on clinica research with patients and datasets, formal didactic training to improve knowledge, and focused mentorship in a strong academic environment at the University of Pittsburgh. She has assembled an excellent experienced mentoring team, including senior investigators in the Renal-Electrolyte Division (Dr. Unruh); Cardiovascular Institute (Dr. Champion and Dr. Teuteberg); Psychiatry, Psychology, Epidemiology and Biostatistics (Dr. Dew); Biostatistics (Dr. Weissfeld); and Critical Care Medicine (Dr. Kellum). This multidisciplinary mentorship team, strong institutional resources and support, and the formal training she will complete under this award will ensure that Dr. Liang continues to develop into a successful independent clinical investigator capable of developing clinical trials and translating that work into clinical care in order to improve outcomes and HRQOL in the cardiorenal failure population. PUBLIC HEALTH RELEVANCE: Combined heart and kidney dysfunction, or cardiorenal failure, is increasingly recognized in patients hospitalized for heart failure (HF) and portends worse mortality. Worsening kidney function occurs in approximately 25-30% of hospitalized HF patients and is associated with worse outcomes and worse health- related quality of life (HRQOL). The aim of this study is to determine if early initiation of ultrafiltration (UF) for flui removal, as opposed to usual clinical care, is associated with improved clinical outcomes and HRQOL in hospitalized cardiorenal failure patients with diuretic resistance. This study will address key gaps in knowledge and will help determine the appropriate treatment strategy and timing of UF in this large population with poor HRQOL, substantial healthcare costs, and high morbidity and mortality.